The macrolides are microbial natural products with many uses in clinical and veterinary medicine. Erythromycin is the best studied example of a macrolide antibiotic; rapamycin and FK506 are promising new immunosuppressant macrolides. The price and availability of macrolides depend on their production efficiency, and therefore, on the genetics of the producing strain. Recently, university studies have shown that increasing copy-number of regulatory antibiotic genes dramatically increases the level of production of model antibiotic compounds. FermaLogic scientists are familiar with the tools required to perform analogous experiments in macrolide-producing organisms. In phase one, we propose to identify and overexpress positive regulators of macrolide production. In phase two, we propose to block competing metabolic pathways and negative regulators using targeted insertion mutations. Ultimately, we will create a collection of yield-improvement products and license them separately to client organizations or combine them into a single FermaLogic strain for high-level macrolide production.